1. Field of the Invention
The present invention relates to a method for treating diseases characterized by connective tissue destruction and, more specifically, to a method for treating articular diseases, characterized by destruction of collagen which is a major constituent of connective tissues.
2. Description of the Prior Art
A variety of diseases are characterized by inflammation and connective tissue destruction. For treatment of these diseases, anti-inflammatory drugs have been used in most cases. In particular, non-steroidal anti-inflammatory drugs (hereinafter referred to as "NSAIDs") have been used for the purpose of suppressing pain and inflammation. The NSAIDs inhibit cyclooxygenase in metabolism of arachidonic acid present in the inflamed sites, thereby inhibiting prostaglandin synthesis. The NSAIDs are therefore considered to have direct analgesic and anti-inflammatory activities.
Immunomodulators are used for suppressing development of articular diseases. Where the conditions have become worse, adrenocorticoids, gold compounds, immunosuppressants and the like are used. Long-term use of adrenocorticoids however induces osteoporosis, while other agents have limited affects.
There has been interest in recent years in developing new drugs that will act by mechanisms different from those of the drugs listed above. A number of studies have been conducted to obtain drugs which will suppress destruction of articular tissues. In the course of the studies, it has been discovered that matrix metalloproteinases, such as collagenase, play an important role in destroying connective tissue [Drugs Fut., 15 495 (1990)]. Antibiotic tetracyclines, such as tetracycline, minocycline and doxycycline, or their salts such as hydrochlorides (hereinafter these compounds are sometimes referred to as "tetracyclines") are known to have a broad antibacterial spectrum. Their activities other than that of an antibiotic nature have also been studied, and in 1983 a research group in State University of New York reported the anti-collagenolytic activity of minocycline in periodontal diseases [J. Periodontal Res., 18, 516 (1983)]. Since then, with the progress of studies on various diseases characterized by collagen destruction, tetracyclines have been studied for clinical application to treat these diseases. Thus, there have been reported treatment with tetracyclines for the following: periodontitis [J. Periodontal Res., 19, 651 (1984)] and J. Dent. Res., 68 (Spec. Issue), 1691 (1989)]; J. Periodontal Res., 25: 321-330 (1990); Corneal Ulcer [Cornea, 3, 75 (1984) and Ann. Ophthalmol., 17, 742 (1985)]; Reiter disease and Lyme disease [Clin. Exp. Rheumatol., 7, 100 (1989) and Annual Internal Med., 99, 22 (1983), respectively] and rheumatoid arthritis [J. Rheumatol., 14, 28 (1987)].
It has also been reported as a result of clinical testing of minocycline on patients suffering from rheumatoid arthritis that appreciable effects were observed 4 months after the start of administration [J. Rheumatol., 17, 43 (1990)].
As a result of knowledge regarding the collagenase-inhibiting activity of tetracyclines, efforts have been made to synthesize tetracycline derivatives. The research group in State University of New York has reported that chemically modified tetracyclines, such as 4-dedimethylaminotetracycline (hereinafter sometimes referred to as "DMAT"), are useful in treatments for rheumatoid arthritis, periodontal diseases and other diseases which require a long-term administration of treating drugs. [See U.S. Pat. No. 4,704,383 (Japanese Patent Application Laid-open No. 243023/1986)]. It has been found that DMAT compares favorably to tetracyclines with respect to collagenase inhibition, suppression of bone resorption, and the like, without the same antibacterial activity [J. Dent. Res., 66, 1310 (1987); J. Cell Biol., 105 Abstracts, abstr. No. 1223 p. 216a (1987) and The 36th Annual Meeting Orth. Res. Soc., abstract p. 268 (1990)].
In 1991, the research group in State University of New York reported that treatment with a combination of a chemically modified tetracycline having anti-collagenase activity but no antibacterial activity, such as DMAT, and an NSAID, such as flurbiprofen, suppressed bone-loss and proved to be effective for tissue-destroying diseases such as rheumatoid arthritis [U.S. patent application Ser. No. 07/445,410 (Japanese Patent Application Laid-open No. 227931/1991)].
Although NSAIDs, which produce analgesic and anti-inflammatory effects by inhibiting prostaglandin synthesis, are effective in suppressing pain and inflammation in articular diseases, they are not known as a remedy for suppressing or retarding the tissue-destructive progress of diseases. NSAIDs now widely used cause gastro-intestinal disorder resulting from inhibition of prostaglandin synthesis.
Accordingly, an object of the present invention is to provide a method of treating humans or animals suffering from a condition or disease characterized by connective tissues destruction, which comprises administering to said human or animal an effective amount of a non-antimicrobial tetracycline derivative or its pharmaceutically acceptable salts having excellent anti-collagenase activity and little toxicity or almost no side effects and being usable in a long-term therapy.
This object as well as other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description.